Tumor necrosis factor a (TNF-.alpha., also cachectin) is an important cytokine that plays a role in host defense. The cytokine is produced primarily in macrophages and monocytes in response to infection, invasion, injury, or inflammation. Some examples of inducers of TNF-.alpha. include bacterial endotoxins, bacteria, viruses, lipopolysaccharide (LPS) and cytokines including GM-CSF, IL-1, Il-2 and IFN-.gamma..
TNF-.alpha. is initially synthesized as a 26 kD membrane-bound protein. A 17 kD fragment of TNF-.alpha. is secreted and forms a trimer with other secreted forms. This trimer interacts with two different receptors, TNF receptor I (TNFRI, p55) and TNFRII (p75), in order to transduce its effects--the net result of which is altered gene expression and/or apoptosis. Cellular factors induced by TNF-.alpha. include interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), interferon-.gamma. (IFN-.gamma.), platelet derived growth factor (PDGF), epidermal growth factor (EGF), and endothelial cell adhesion molecules including endothelial leukocyte adhesion molecule 1 (ELAM-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (Tracey, K. J., et al., Annu. Rev. Cell Biol., 1993, 9, 317-343; Arvin, B., et al., Ann. NY Acad. Sci., 1995, 765, 62-71).
The processing of TNF-.alpha. from its membrane-bound form to its secreted form is due to a specific metalloprotease known as TNF-.alpha. converting enzyme (TACE, also ADAM17). TACE is a member of the ADAM (A Disintegrin And Metalloprotease) family. TACE has also been shown to have a direct proteolytic role in the processing of other membrane proteins including p75 TNF receptor, L-selectin and transforming growth factor-.alpha. (TGF-.alpha.; Peschon, J. J., et al., Science, 1998, 282, 1281-1284). L-selectin, in particular, is an adhesion molecule involved in leukocyte rolling and mediates the attachment of leukocytes to endothelium at sites of inflammation as well as the binding of lymphocytes to high endothelial venules of peripheral lymph nodes.
Inhibitors of TACE will inhibit release of TNF-.alpha. into the extracellular environment, preventing TNF-.alpha. mediated signaling. Thus, TACE inhibitors may have clinical utility in diseases associated with the over-production of TNF-.alpha.. Additional utility may be present in regulating the processing of other membrane-bound TACE substrates, such as TGF-.alpha., which has been shown to be involved in many cancers and psoriasis (Kumar, V., et al., Cell Biol Int., 1995, 19, 373-388) and the .beta.-amyloid precursor protein.
Overexpression of TNF-.alpha. often results in disease states, particularly in infectious, inflammatory and autoimmune diseases. This process may involve the apoptotic pathways (Ksontini, R., et al., J. Immunol., 1998, 160, 4082-4089). High levels of plasma TNF-.alpha. have been found in infectious diseases such as sepsis syndrome, bacterial meningitis, cerebral malaria, and AIDS; autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease (including Crohn's disease), sarcoidosis, multiple sclerosis, Kawasaki syndrome, graft-versus-host disease and transplant (allograft) rejection; organ failure conditions such as adult respiratory distress syndrome, congestive heart failure, acute liver failure and myocardial infarction (Eigler, A., et al., Immunol. Today, 1997, 18, 487-492). Other diseases in which TNF-.alpha. is involved include asthma (Shah, A., et al., Clinical and Experimental Allergy, 1995, 25, 1038-1044), brain injury following ischemia (Arvin, B., et al., Ann. NY Acad. Sci., 1995, 765, 62-71), non-insulin-dependent diabetes mellitus (Hotamisligil, G. S., et al., Science, 1993, 259, 87-90), insulin-dependent diabetes mellitus (Yang, X.-D., et al., J. Exp. Med., 1994, 180, 995-1004), hepatitis (Ksontini, R., et al., J. Immunol., 1998, 160, 4082-4089), atopic dermatitis (Sumimoto, S., et al., Arch. Dis. Child., 1992, 67, 277-279), and pancreatitis (Norman, J. G., et al., Surgery, 1996, 120, 515-521). Further, Suganuma, M., et al. (Cancer Res., 1996, 56, 3711-3715) suggest that inhibitors of TNF-.alpha. may be useful for cancer prevention. In addition, elevated TNF-.alpha. expression may play a role in obesity (Kern, P. A., J. Nutr., 1997, 127, 1917S-1922S). TNF-.alpha. was found to be expressed in human adipocytes and increased expression, in general, correlated with obesity.
L-selectin has been found to be involved in ischemia/reperfusion injury, especially myocardial (Ma, X.L., et al., Circulation, 1993, 88, 649-658), and liver (Yadav, S. S., Am. J. Physiol., 1998, 275, G1341-G1352) and thromboembolic stroke (Bednar, M. M., et al., Neurol. Res., 1998, 20, 403-408); acute myeloid leukemia (Extermann, M., et al., Blood, 1998, 92, 3115-3122), B-cell chronic lymphocytic leukemia (Csanaky, G., et al., Haematologica, 1994, 79, 132-136); experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (Archelos, J. J., et al., J. Neurol. Sci., 1998, 159, 127-134), human T-cell lymphotropic virus type I-associated myelopathy (Tsujino, A., et al., J. Neurol. Sci., 1998, 155, 76-79), meningoencephalitis (Buhrer, C., et al., Arch. Dis. Child., 1996, 74, 288-292); rheumatoid arthritis (Kurohori, Y., et al., Clin. Rheumatol., 1995, 14, 335-341), ulcerative colitis (Seidelin, J. B., et al., Am. J. Gastroenterol., 1998, 93, 1854-1859); chronic lung disease (Kotecha, S., et al., Arch. Dis. Child. Fetal Neonatal Ed., 1998, 78, F143-F147).
There are currently several approaches to inhibiting TNF-.alpha. expression. Approaches used to treat rheumatoid arthritis include a chimeric anti-TNF-.alpha. antibody, a humanized monoclonal anti-TNF-.alpha. antibody, and recombinant human soluble TNF-.alpha. receptor (Camussi, G., Drugs, 1998, 55, 613-620). Other examples are indirect TNF-.alpha. inhibitors including phosphodiesterase inhibitors (e.g. pentoxifylline) and metalloprotease inhibitors (Eigler, A., et al., Immunol. Today, 1997, 18, 487-492). An additional class of a direct TNF-.alpha. inhibitor is oligonucleotides, including triplex-forming oligonucleotides, ribozymes, and antisense oligonucleotides.
Inhibitors of L-selectin include monoclonal antibodies (Bednar, M. M., et al., Neurol. Res., 1998, 20, 403-408), fucoidin (Nasu, T., et al., Immunol. Lett., 1997, 59, 47-51), and oligonucleotide aptamers (Ringquist, S. and Parma, D., Cytometry, 1998, 33, 394-405).
Although broad spectrum inhibitors of matrix metalloproteases are effective in inhibiting TACE, specific inhibitors are desired for clinical use.
U.S. Pat. No. 5,629,285 describes small molecule inhibitors of TACE based on peptidyl derivatives. WO 96/41624 describes the use of antisense oligonucleotides to block expression of TACE, but no oligonucleotide sequences were disclosed.
There remains an unmet need for therapeutic compositions and methods targeting expression of TACE, and disease processes associated therewith.